Xanthone carboxylic acids and derivatives

ABSTRACT

Compositions containing and methods employing, as the essential ingredient, xanthone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions are also disclosed. 7Acetylxanthone-2-carboxylic acid is illustrated as representative of the class.

United States Patent [1 1 Pfister et a1.

[ 1 Mar. 25, 1975 XANTHONE CARBOXYLIC ACIDS AND DERIVATIVES Inventors:

Assignee:

Filed:

Appl. No.:

Jurg 1R. Pfister, Los Altos; Ian T.

Harrison; John 1 1. Fried, both of Palo Alto, all of Calif.

Syntex (U.S.A.) Inc., Palo Alto,

Calif.

Jan. 12, 1972 Related U.S. Application Data Continuation-impart of Ser. No. 162,696, July 14,

1971, abandoned.

U.S. C1 424/283, 424/251, 424/263,

424/269, 424/272, 424/274, 424/275 Int. Cl A6lk 27/00 Field of Search 424/283 References Cited UNITED STATES PATENTS Doebel et a1. 260/335 3,073,847 1/1963 Doebel et a1. 260/328 3,126,411 3/1964 Bellet et a1 260/5708 3,467,623 9/1969 Hindcrer et a1 260/47 3,642,997 2/1972 Shen ct a1. 424/250 3,678,077 7/1972 Nakanishi et a1. 260/335 3,706,768 12/1972 Bays 124/2143 FOREIGN PATENTS OR APPLlCATlONS 773,649 5/1971 Belgium Primary Examiner-Albert T. Meyers Assistant Examiner-Norman A. Drezin Attorney, Agent, or FirmGerard A. Blaufarb; Walter H. Dreger; William B. Walker 10 Claims, N0 Drawings ing and methods utilizing these compounds as the es- 1 2 XANTHONE CARBOXYLIC ACIDS AND these symptoms, the method hereof serves to inhibit DERIVATIVES the effects of the allergic reaction when administered This isa continuation-in-part of application Ser. No. in an effective amount. While not intending to be 162,696, filed l4 July 1971, now abandoned. bound by any theoretical mechanism of action, the

nae present invention is dir'e eied to 'saaiiiane car 5 methcd is beliived by inhibiting. the

release and/or the action of toxic products, e.g-. histamine, -hydroxytryptamine, slow releasing substance (SRS-A), and others, which are produced as a result of a combination of specific antibody and antigen (allergic) reaction. These properties make the subject cam I g V H g V pounds particularly useful in the treatment of various In a first aspect, the present invention relates to novel allergic conditions.

boxylic acid compounds and to compositions containsential ingredient in the treatment of symptoms associated with allergic manifestations, for example, asthmatic conditions.

xanthone carboxylic acid compounds selected from This aspect of the present inventionthus relates to 21 those represented by the following formulas: method useful for inhibiting the effects of the allergic R coon and the pharmaceutically acceptable, non-toxi esters, ieaction which comprises administering an effectivei amides and salts thereof; wherein each R is a group Se- 25 amount of a compound selected from those repre-' lected from those of the formulas:- sented by the following formulas:-

and the pharmaceutically acceptable non-toxic esters,-

l cllfi/R g 2 amides, and salts thereof; wherein each R is a group se- Z .lected from those of the formulas:-

40 i 7 V 7 OH 1 0 in which R is hydrogen, lower alkyl or cycloalkyl, and la 2 R is hydrogen; lower alkyl; cycloalkyl; halomethyl; I R

phenyl; substituted phenyl in which the substituent is' halo, lower alkyl, lower alkoxy, lower alkylthio, tr'ifluo- 4 romethyl, or cyano; or a monocyclic aromatic heterocyclic group having five or six total members, one or two of which are selected from nitrogen, oxygen, and

5 in which R is hydrogen, lower alkyl or cycloalkyl, and R is hydrogen; lower alkyl; cycloalkyl; halomethyl; phenyl; substituted phenyl in which the substituent is halo, lower alkyl, lower alkoxy, lower alkylthio, trifluosulfur romethyl, or cyano; or a monocyclic aromatic hetero- Thus included within the scope of the present inven- Cyclic fP having fi or six tofal members one or on are the 5 and 7 secondary and tertiary two of which are selected from nitrogen, oxygen, and hydroxyalkyl substituted xanthone-2-carboxylic acid Sulfer Pf pharmacutlcally acceptable non'toxlc compounds and the C-5 and C-7 acyl substituted .Fomposmon mcorporatlrlg Slld Compounds, estersv xanthone-2-carboxylic acid compounds. Salts as P" F l f The present invention, in a third aspect. IS directed In a second aspect. the present invention is directed to pharmaceutical compositions useful for inhibiting to a method useful for relieving symptoms .associated the effects of the allergic reaction comprising an effecwith allergic manifestations such as are brought about tive amount of a compound selected from those repre by antigen-antibody (allergic) reactions. In the relief of sented by the following formulas:-

OOH

and the pharmaceutically acceptable esters, amides, and salts thereof; wherein each R is a group selected from those of the formulas:-

amount ranges from about 0.005 to about 100 mg. per

COOH

kgjof body weight per day and preferably from about 0.01 to about 100 mg, per kg. of body weight per day. In alternate terms, an effective amount in accordance OH 1 herewith generally ranges from about 0.5 to about fl 2 7000 mg. per day per subject.

Useful pharmaceutical carriers for the preparation of a v the compositions hereof, can be solids, liquids, or in which R is hydrogen, lower alkyl or cycloalkyl, gases. Thus, the compositions can take the form of taband R is hydrogen; lower alkyl; cyeloalkyl; halomethyl; l0 lets, pills, capsules, powders, sustained release formulaphenyl; substituted phenyl in which the substituent is tions, solutions, suspensions. clixirs. aerosols, and the halo, lower alkyl, lower alkoxy, lower alkylthio, trifluo- 4 like. The carriers can be selected from the various oils r m hyl, Y i1 n y i ammlllic including those of petroleum, animal, vegetable, or syncyclic group having five r iX tota m rs. n 0 thetic origin, for example, peanut oil, soybean oil, mint f hich a s d r m n g xyg n. and eral oil, sesame oil, and the like. Water, saline, aqueous ulfur. in admixture with a pharmaceutically acccpt dextrose, and glycols are preferred liquid carriers, parable non-toxic carrier. ticularly for injectable solutions. Suitable pharmaceuti- In the pra tice of the met d 0f h P s n cal excipients include starch, cellulose, talc, glucose, tion, an effective amount ofa compound of the present l sucrose, l tin, malt, ri e, flour, chalk, silica invention or pharmaceutical compositions thereof. as l magnesium carbonate, magnesium stearate dcfined 'fi is administered Vii! y of the usual and dium stearate, glyceryl monostearate, sodium chloride. acceptable methods known in the art, either singly ord i d ki ilk glycerol, propylene glycol water, min Combination with another c0mlmund or compounds anol, and the like. Suitable pharmaceutical carriers and 0f the Present invention or mher Pharmaceutical their formulation are described in Remingtons Pharagems, Such as antlbiotlc5- hormonal g and 50 maceutical Sciences by E. W. Martin. Such composifOFIh' These mp ds mp n can thus be tions will, in any event, contain an effective amount of administered orally, topically, parenterally, or by inhathe active compound together with a suitable amount lation and in the form of either solid, liquid, or gaseous f ie so as to re are the proper dosage form for dosages including tablets, suspensions, and aerosols, as proper d i i i [0 the ho t, discussed in more detail hereinafter. The administration can be conducted in single unit dosage form with The 9 the present mvemlon demon- Contimmus therapy or in Single dose themp), ad libitum, strate activity as ll'lhlbllOlS of the effects of the allergic f bl m h lactica" reaction as measured by tests ll'lCllCZlIlVC of such activity P y py y ln view of the foregoing as well as in consideration of Passwe Cutaneous anaphyldfls substanthe degree or severity of the condition being treated, descnbed for Example by Goose at lmmu' age of subject, and so forth, all of which factors being nology 749 (1969) determinable by routine experimentation by one skilled Certain of the compounds of the present invention in the art, the effective dosage in accordance herewith can be prepared in accordance with the following reaccan vary over a wide range. Generally, an effective tion sequence:

Seguence A R l I 3 DDR COOR 3 halo COOR

COOH (4) COOH wherein R" is lower alkyl, preferably methyl;

R is acyl; and

halo is bromo, chloro, fluoro, or iodo, preferably bromo.

With reference to the above sequence, an ortho or para substituted (R phenol (l) is condensed with the l,3-dicarbo(lower)alkoxy4-halobenzene compound (2) in the presence of cuprous oxide optionally in organic liquid reaction medium, preferably an organic amide such as dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidone, tetramethylurea, and so forth, to prepare the corresponding l,3-dicarbo(lower- )alkoxy-4- (oor p-substituted phenyloxy)-benzene compound (3).

The reaction is preferably conducted in an inert organic reaction medium, such as those listed above, or suitable mixtures of one or more of such medium. The reaction is further conducted at temperatures ranging from about 80 to about 220C, preferably about from 120 to 200C, and for a period of time sufficient to complete the reaction, ranging from about two hours to about 24 hours.

The reaction consumes the reactants on the basis of one mole of the substituted phenol per mole of the diearbo(lower)carboxyhalobenzene per half mole of cuprous oxide. However, the amounts of the reactants to be employed are not critical, some of the desired compound (3) product being obtained when employing any proportions thereof. In the preferred embodiments, the reaction is conducted by reacting from about one to about three moles of the substituted phenol compound with about from one to about 12 moles of the dicarbo- (lower)carboxyhalobenzene compound in the presence of from about 0.5 to about 0.6 moles of the cuprous oxide. The inert organic reaction medium, if employed, is used in solvent amounts.

Thereafter, the prepared compound (3) is base bydrolyzed to give the corresponding l,3-dicarboxy-4-(o or p-substituted phenyloxy)-benzene (4). The base bydrolysis conditions can be any employed conventiom ally in the art. Generally, the hydrolysis reaction is conducted using an alkali metal hydroxide at about 50 to about 90C and for a period of time sufficient to complete the reaction, ranging from about 15 minutes to about 60 minutes. preferably in the presence of inert organic reaction media such as those normally employed in organic chemical reactions of this type. eg. aqueous alkanol solutions. Although two moles of base are required per mole of compound (3). the amounts employed are not critical to produce the desired hydrolysis. Preferably from about three to about five moles of base are employed per mole of compound (3) and the reaction media, if employed, is used in solvent amounts.

The thus prepared diacid compound (4) is then cyclized with phosphoryl chloride, thionyl chloride, sulfuric acid, hydrogen fluoride, or preferably, polyphosphoric acid (PPA), to give the corresponding 5- or 7- substituted xanthone-Z-carboxylic acid compound (5). The reaction is preferably, but optionally, conducted in an inert organic reaction medium including those usually employed in organic chemical reactions, such as dimethylsulfoxide, sulfolane, benzene, toluene, and so forth. The reaction is further conducted at temperatures ranging from about to about lC, and for a period of time sufficient to complete the reaction ranging from about 15 minutes to about minutes.

Although the reaction consumes the reactants on the basis of one mole of compound (4) per mole of cyclizing reagent, the reaction can be performed using any proportions of reactants. In the preferred embodiments, however, the reaction is conducted using from about 20 to about 50 moles ofthe cyclizing reagent per mole of starting compound (4).

The compounds of the present invention in the 5- or 7-(secondary hydroxyalkyl)-xanthone-2-carboxylic acid series are prepared from the corresponding 5- or 7-acyl compounds, prepared as described above The 5- or 7-acylxanthone-2-carboxylic acids are converted to the corresponding acid ester such as with alkyl iodide under basic conditions. The acyl ester is then reduced such as with sodium borohydride to give the 5- or 7-(secondary hydroxyalkyl)-xanthone-2-carboxylic acid ester which can be hydrolyzed to the acid.

The 5- or 7-(tertiary hydroxyalkyl)-xanthone-2- carboxylic acids hereof are prepared by treating the 5- or 7-acylxanthone carboxylic acid esters with a lower alkyl or cycloalkyl Grign ard reagent followed by hydrolysis of the ester.

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

Seguence B- Continued o 3 3 2' I Q COOR O COOH wherein R" is R exclusive of hydrogen, R is R exclusive of hydrogen. and R is lower alkyl, preferably methyl.

With reference to the above reaction sequence, xanthone-Z-carboxylic acid (6) prepared as described above, is reduced such as with potassium hydroxide in hydrazine, zinc and potassium hydroxide in ethanol, lithium aluminum hydride, and like reduction methods to prepare the corresponding xanthene-Z-carboxylic acid (7). This compound is conventionally esterified (R'') by means known to those skilled in the art, for example, by treatment of the acid with diazoalkane or with alkanol and sulfuric acid. The resultant ester (8) is then acylated under Friedel-Crafts conditions with an acid chloride in the presenceof aluminum chloride to give the corresponding 7-acyl compound (9).

The resultant compound (9) is oxidized, such as under known Jones conditions. to give the corresponding 7acylxanthone-Z-carboxylate esters (10), which can be hydrolyzed, as described above, to give the 7-acylxanthone-Z-carboxylic acid compounds l Compounds can also be reduced. such as by the known method using sodium borohydride. to give the corresponding 7-(secondary hydroxyalkyl)-xanthone- COOH cooH

2-carboxylate esters (l l which can he hydrolyzed to the acid products (13),

Compounds 10) can also be treated with alkyl or cycloalkyl (i.e. R" Grignard reagent, under known Grignard reaction conditions, to give the corresponding 7-(tertiary hydroxyalkyl)-xanthone-2-carboxylate esters (12) which can be hydrolyzed to the acid products 14).

Alternatively, the compounds of formulatl) can be reduced or treated with Grignard reagent, as described Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

' COOR 3 (8) (16) on i O I OOR CI'QH CILCH 3 OHC 3 /CH 00R 00R e3 O OHC OOH With reference to the above reaction sequence, xanthene-Z-carboxylic acid ester (8) is reacted with chloroacctyl chloride under Friedel-Crafts conditions to give compound (l6). This compound is then oxidized as described above to give the corresponding xanthone (17) which is reduced as described above to give the hydroxy compound (18). The resultant compound is treated with sodium hydride in dimethylformhalo 3 COOR Continued COOH COOH CH I CH2 COOH 2 3/ 2 OOH COOH CH-OH 2' 2' COOH C-OH 2 1' R R wherein each of R" R R. and halo is as above defined. 40 2 CH--Br) With reference to the above reaction sequence, the -substituted-xanthone-2-carboxylic compounds are prepared following the above reaction Sequence A (1+2 3 4 S) with the respective starting compounds (22). The resultant compounds (25) or their esters are oxidized with chromium trioxide in acetic ucid'ucetic anhydride to give the S-acyl compounds (2(a) which are reduced or treated with Grignard reagent as above described to give the respective 5- (secondary and tertiary hydroxyalkyl)-x-anthone-2- carboxylic acid products (27 and 28). Alternative to the above procedure, the S-substituted xanthone-Z- carboxylic acid (25) can be converted to its corresponding ester and it treated with N-bromosuccinimide to prepare the corresponding 5-(substituted bromomethyl) compound (i.e.

which can be converted to the corresponding alcohol upon treatment with aqueous base, to give the product acids (27).

A particularly preferred method for the preparation of certain of the compounds hereof is represented as follows:

Seguence E e i ysd.--

wherein R is as defined above.

With reference to the above sequence, an appropriate phenol (29) is treated with 1,3-dimethyl-4-halo- (preferably iodo) benzene (30), as described above, to prepare the corresponding 1,3-dimethyl-4-phenyloxy benzene (31). This compound is then oxidized such as with potassium permanganate in aqueous tbutanol, to give the corresponding l,3-dicarboxy-4-phenyloxybenzene (32). This compound is then cyclized, as described above, to give the corresponding xanthone-Z- carboxylic acid (33) which can be modified as described above to prepare the product C- or C-7 substituted compounds hereof.

The acid esters of the xanthone-Z-carboxylic acids hereof are prepared as described above (eg 7 8) upon treatment of the acid with ethereal diazoalkane such as diazomethane and diazoethane or with the desired lower alkyl iodide in the presence of lithium carbonate at room temperature or with the desired lower alkanol'in the presence of a trace of sulfuric acid at reflux. The glycerol esters are prepared by treating the acid with thionyl chloride followed by treatment with a suitably protected ethylene glycol or propylene glycol (e.g. solketal) in pyridine, and hydrolyzing the protecting group of the ester thus formed with dilute acid. In 'the sulfo series, the carboxylic acid esters are preferably prepared with the desired lower alkanol in the absence of acid catalyst.

The amides of the xanthone-Z-carboxylic acids hereof are prepared by treatment of the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkyl, amine, dialkyl amine, dialkylaminoalkyla mine, alkoxyalkylamine, or phenethylamine.

The salts of the xanthone-Z-carboxylic acids hereof are prepared by treating the corresponding acids with pharmaceutically acceptable base. Representative salts derived from such pharmaceutically acceptable bases are sodium, potassium, lithium, ammonia, calcium,

magnesium, ferrous, ferric, zinc, manganous. aluminum, manganic, the salts of trimethylamine, triethylamine, tripropylamine, ,B-(dimethylamino)ethanol, triethanolamine, ,B-(diethylamino)ethanol, arginine, lysine, histidine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine. glucosamine, methyl glucamine, theobromine, purines, piperazine. piperidine. polyamine resins, caffeine, procaine or the like. The reaction is conducted in an aqueous solution. alone or in sqmbin iwi wit an inert st rmi ibl 9 .29.1119 $91.

COOH

COOH

vent, at a temperature of from about 0C to about C, preferably at room temperature. Typical inert. water miscible organic solvents include methanol. ethanol, isopropanol, butanol, acetone. dioxane, or tetrahydrofuran. When divalent metal salts are prepared. such as the calcium salts or magnesium salts of the acids the free acid starting material is treated with about one half molar equivalent of pharmaceutically acceptable base. When the aluminum salts of the acids are prepared about one third molar equivalent of the pharmaceutically acceptable base are employed.

In the preferred embodiment of the present invention, the calcium salts and magnesium salts of the acids are prepared by treating the corresponding sodium or potassium salts of the acids with at least one half molar equivalent of calcium chloride or magnesium chloride, respectively, in an aqueous solution, alone or in combination with an inert water miscible organic solvent, at a temperature of from about 20C to about 100C.

In the preferred embodiment of the present invention, the aluminum salts of the acids are prepared by treating the acids with at least one third molar equivalent of an aluminum alkoxide, such as aluminum triethoxide, aluminum tripropoxide and the like, in a hydrocarbon solvent, such as benzene, xylene, cyclohexane, and the like at a temperature of from about 20C to about C.

The starting compounds for use in the present invention are known and can be prepared in accordance with known procedures. Thus, the 1,3- dicarbo(lower)alkoxy-4-halobenzene starting compounds (2) are conveniently prepared by oxidizing l,3-dimethyl-4-halobenzene (4-halom-xylene) with potassium permanganate, as described above (31 32), followed by conventional esterification. The 0- or p-acylphenols (1 are conveniently prepared by performing a Friedel-Crafts reaction with phenol to give the desired acylphenol compounds which can be separated such as by steam distillation. The acyl group thereof is reduced with platinum oxide or palladium catalyst in the presence of perchloric acid in ethanol. Lower alkoxyphenylcarboxylic acid chloride acylating agents for the preparation of alkoxyphenylcarbonylphenol starting compounds, are prepared, for example, by selectively esterifying hydroxybenzoic acid with methanol and a trace of sulfuric acid or with lithium carbonate and methyl halide in dimethylformamide.

The resultant hydroxybenzoate ester is then conventionally alkylated with lower'alkylhalide and potassium carbonate followed by selective hydrolysis of the ester of the carboxylic acid group and conversion' to the acid chloride with, e.g., thionyl chloride.

In the present specification and claims, by the term lower alkyl is intended a lower alkyl group containing one to eight carbon atoms including straight and branched chain groups, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, sec-pentyl, t-pentyl, n-hexyl, npentyl, n-octyl, isooctyl. The term cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. By the term lower alkoxy is intended the group O-lower alkyl wherein lower alkyl is as defined above. By the term lower alkylthio is intended the group S-lower alkyl wherein lower alkyl" is as defined above. The term substituted phenyl" includes p-sutstituted phenyl. The term monocyclic aromatic heterocyclic group includes pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidozolyl, furanyl, thiophenyl, pyrrolyl, isoxazolyl, and oxazolyl. By the term "halomethyl is meant trifluoromethyl, trichloromethyl, difluoromethyl, and dichloromethyl.

By the term pharm aceutically acceptable, nos-taxi? esters, amides, and salts" is respectively intended an alkyl or glycerol ester; an unsubstituted, monoalkyl, di alkyl, dialkylaminoalkyl, alkoxyalkyl, or phenethyl substituted amide and a salt as defined above.

In the secondary and tertiary hydroxyalkyl series the compounds may possess a chiral center. The methods hereof generate each of the d and l and dl forms and each is thus included within the scope hereof. lf desired, the iosmers can be separated by conventional means such as forming the alkaloid salts of the products and employing fractional crystallization.

The nomenclature herein is employed in accordance with Chemical Abstracts 56 Subject Index 1962, January-June).

The following examples illustrate the method by which the present invention can be practiced.

EXAMPLE 1 A mixture of 3.9 g of 1,3-dicarbomethoxy-4- bromobenzene, 2.85 g. of p-acetylphenol, 1.1 g. of cuprous oxide, and 25 ml. of tetramethylurea is heated to 165C and maintained thereat with stirring for 18 hours under a nitrogen atmosphere. After this time, the reac' tion mixture is diluted with water and extracted with ether. The extracts are dried and evaporated to give 1,- 3-dicarbomethoxy-4-(p-acetylphenyloxy)-benzene.

l,3-Dicarbomethoxy-4-(p-acetylphenyloxy)-benzene (3.5 g.) is dissolved in 50 ml. of ethanol and the mixture treated with ml. of 4 percent aqueous potassium hydroxide solution. The reaction mixture is refluxed for 30 minutes, concentrated under reduced pressure, and acidified with dilute hydrochloric acid. The solid collected upon filtration is washed with water and dried to give l,3-dicarboxy-4-(p-acetylphenyloxy)- benzene which is recrystallized from ethanol-water.

A solution of 3.2 g. of 1,3-dicarboxy-4-(p-acetylphenyloxy)-benzene in 30 ml. of concentrated sulfuric acid is warmed to 80C. The mixture is then allowed to stand at room temperature for 16 hours after which time it is poured into ice water, filtered, washed and dried to give 7-acetylxanthone-2-carboxylic acid which is recrystallized w from tetrahydrofuran-ethanol. M The foregoing method can also be employed using an alternative 1,3-carboloweralkoxy-4-halo starting compound such as l,3-dicarbomethoxy-4-chloro or iodo benzene, l,3-dicarboethoxy-4-fluoro benzene, 1,3-dicarboethoxy-4-bromo benzene, and the like, with similar results.

in a similar manner, the above described reactions can be conducted utilizing an alternate p-acyl phenol starting material to give the. corresponding 7-acyl-xanthone-2-carboxylic acid products, cg. 7-formylxanthone-2-carboxylic acid. 7 propionylxanthone-Z-carboxylic acid, 7-nbutyrylxanthone-Z-carboxylic acid, 7- isobutyrylxanthone-Z-carboxylic acid, 7-npentanoylxanthone-Z-carboxylic acid, 7- isopentanoylxanthone-2-carboxylic acid, 7-secpentanoylxanthone-Z-carboxylic acid. 7-tpentanoylxanthone-Z-carboxylic acid. 7- hexanoylxanthone-2-carboxylic acid, 7- heptanoylxanthone-2-carboxylic acid. 7' octanoylxanthone-2-carboxylic acid, 7- nonanoylxanthone-2-carboxylic acid. 7- cyclopropylcarbonylxanthone-Z-carboxylic acid. 7- cyclobutylcarbonylxanthone-Z-carboxylic acid. 7- cyclopentylcarbonylxanthone-2-carboxylic acid, 7- cyclohexylcarbonylxanthone-2-carboxylic acid, 7- haloacetylxanthone-2-carboxylic acid, 7- benzoylxanthone-Z-carboxylic acid, 7-substituted benzoylxanthone-Z-carboxylic acid, and 7- heterocycliccarbonylxanthone-2-carboxylic acid.

The procedure of Example 1 is repeated using the appropriate o-acyl phenol starting compounds to prepare the corresponding 5-substituted xanthone-Z-carboxylic acid, to wit, 5-formylxanthone-2-carboxylic acid, 5-acetylxanthone-2-carboxylic acid, 5- propionylxanthone-2carboxylic acid, 5-nbutyrylxanthone-2-carboxylic acid, 5-

isobutyrylxanthone-2-carboxylic acid, and so forth.

EXAMPLE 2 To a solution of 25 grams of xanthone-2-carboxylic acid (prepared as described in Example'l from 1,3-

-dicarbomethoxy-4-bromobenzene and phenol) in 200 ml. of triethylene glycol are added 18 g. of potassium hydroxide and 12.1 g. of 95 percent hydrazine. The resultant mixture is heated to reflux (155C) and maintained thereat for one hour. The distillate is removed and the temperature is held at a temperature of about 200C for 2 hours. The mixture is then cooled to 68C and 200 ml. of water is added and the resultant solution poured into 1 10 ml. of water containing ml. of concentrated hydrochloric acid. The resultant mixture is heated to C, cooled to room temperature and filtered to give xanthene-Z-carboxylic acid.

26 Grams of xanthane-2-carboxylic acid is added to 400 ml. of absolute methanol. To the resultant solution are added 18 ml. of concentrated sulfuric acid and the mixture is then heated at reflux for about two hours.

The mixture is then cooled to 40C and sufficient water is added to bring the total volume to 1400 ml. The resultant mixture is then filtered to give methyl xanthene- 2-carboxylate.

A mixture of 13.0 g. of methyl xanthene-2- carboxylate in 200 ml. of dichloroethane is cooled to -5C and to the cooled solution are added 4.95 ml. of acetyl chloride and then 17.0 g. of aluminum trichloride Theresultant solution is stirred at room temperamethylene chloride. The combined extracts are washed with aqueous potassium hydroxide solution and the washed solution evaporated to give methyl 7- acetylxanthene'2-carboxylate.

To a solution of 1.42 g. of methyl 7-acetylxanthene- 2-carboxylate in 120 ml. of acetone and ml. of dimethylformamide are added 3.0 g. of magnesium sulfate and 2.5 ml. ofSN chromic acid in 8N sulfuric acid.

The resultant mixture is stirred at room temperature for 50 minutes after which time a solution of4 g. of sodium bisulfite in ml. of water is added. After this time, 250 ml. of water and ml. of sulfuric acidzwater (1:1) are added. The mixture is stripped of solvent and filtered. The precipitate is washed with 5.0 ml. of water to give methyl 7acetylxanthone-2-carboxylate which is recrystallized from methanol (displacement from methylene chloride solution).

A solution of 2 g. of methyl 7-acetylxanthone-2- carboxylate in 200 ml. of 10% aqueous, 10 percent potassium hydroxide in methanol is heated at reflux under a nitrogen atmosphere for minutes. After this time, 20 ml. of water are added and the resultant mixture heated at reflux for 35 minutes. Water (300 ml.) is then added and the resultant mixture acidified and filtered to give 7-acetylxanthonel2-carboxylic acid.

EXAMPLE 3 The procedure of Example 2 is repeated employing, in the procedure of the third paragraph thereof, the acyl chlorides (prepared from the corresponding acids upon treatment with thionyl chloride or oxalyl chloride) listed in Column A below to prepare the corre sponding acid products listed in Column B below, through their respective methyl esters.

Column A Column B propionyl chloride n-butyryl chloride isobutyryl chloride n-pentanoyl chloride sec-pentanoyl chloride t-pentanoyl chloride n-hexanoyl chloride n-heptanoyl chloride 7-n-octanoylxanthone2-carboxylic acid 7-n nonanoylxanthone-2-carboxylic acid 7cyclopropylcarbonylxanthone-Z- car oxylic acid 7-cyclobutylcarbonylxanthone-Z- carboxylic acid 7-cyclopentylcarbonylxanthone-Z- carboxylic acid 7-c clohexylcarbonylxanthone'2- car oxylic acid 7-trifluoroacetylxanthone-Z-carboxylic acid 7-difluoroacetylxanthone-Lcarboxylic acid 7-trichloroacetylxanthone-Z-carboxylic n-octanoyl chloride n-nonanoyl chloride cylclopropylcarbonyl c loride cyclobutylcarbonyl chloride cyclopentylcarbonyl chloride cyclohexylcarbonyl chloride tritluoroacetyl chloride 7 difluoroacetyl chloride trichloroacetyl chloride acid 7-dichloroacetylxanthone-Z-carhoxylic acid 7-benzoylxanthone-2-carboxylic acid 7-(p-chlorohenzoyl)xanthone 2- carboxylic acid 7-(p-methylbenzoyl)xanthone-Z- carboxylic acid dichloroacetyl chloride benzoyl chloride p-chlorobenzoyl chloride p-methylbenzoyl chloride 'p-methoxybenzoyl chloride Continued Column A (olumn B l-( -methoxyncnl.oyl)xanthone-lcar oxylic acid 7-(p-thiomethoxylmmoyl)xanthonc-Z- carboxylic acid 7-furoylxanthonc-Z-carhoxylic acid 7pyrroylxanthonc-2-carhoxylic acid 7-thcnoylxanthone-Z-carhoxylic acid 7-pyridylcnrhonylxanthoncQ-carhoxylic aci imidazolylcarhonyl chloride 7-imidazolylcarhonylxanthone2- carboxylic acid loxazolylcarbonylxanthone-Z- carboxylic acid p-thiomethoxyhenzoyl chloride furoyl chloride pyrroyl chloride thenoyl chloride pyridylcarbonyl chloride oxazolylcarbonyl chloride The foregoing is practiced using the corresponding acyl bromide starting compounds, with similar results.

EXAMPLE 4 A mixture of 1.077 g. of methyl 7-acetylxanthonel2- carboxylate, 200 mg. of sodium borohydride and 150 ml. of tetrahydrofuran is stirred for 2.5 hours at room temperature. The reaction is monitored by tlc. After this period of time, a 5% aqueous acetic acid solution is added to the reaction mixture dropwise to neutrality and the resultant solution evaporated under vacuum and crystallized by the addition of ethanol and hot water. The precipitate is filtered off. washed and dried to give methyl 7-( l-hydroxyethyl )-xanthone-2- carboxylate.

A mixture of 860 mg. of methyl 7-( l hydroxyethyhxanthone-Z-carboxylate, 60 ml. of ethanol and 2 ml. of 2N sodium hydroxide is refluxed for 30 minutes. The resultant mixture is cooled, acidified and the precipitate is filtered off, washed, and dried to give 7-(1- hydroxyethyl)'-xanthone-2-carboxylic acid.

The foregoing procedures are practiced upon the other 7-acyl methyl esters prepared as described in Example 3 to give the following products, through their respective methyl esters:

7-( l-hydroxy-n-propyl)-xanthone-2 carboxylic acid,

7-( l-hydroxy-n-butyl)-xanthone-2-carboxylic acid,

7-(1-hydroxyisobutyl)-xanthone-2-carboxylic acid,

7-( l-hydroxyn-pentyl)-xanthone-2-carboxylic acid,

7'( l-hydroxy-isopentyl)-xanthone-2carboxylic acid,

7-( l-hydroxy-sec-pentyl )-xanthone-2-carboxylic acid,

7-( l-hydroxy-t-pentyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-hexyl)-xanthone-2-carboxylic acid,

7-(l-hydroxy-n-heptyl)-xanthone-2-carboxylic acid,

7-(l-hydroxy-n-octyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-nonyl)-xanthone-2-carboxylic acid,

7-( (cyclopropyl)hydroxymethyl )-xanthone-2- carboxylic acid, 7-((cyclobutyl)hydroxymethyl)-xanthone-2- carboxylic acid, 7-((cyclopentyl)hydroxymethyl)-xanthone2- carboxylic acid, 7-((cyclohexyl)hydroxymethyl)xanthone-2- carboxylic acid, 7-(2,2,2-trifluoro-l-hydroxyethyl)-xanthone-2- carboxylic acid, 7-(2,2-difluoro-l-hydroxyethyl)-xanthone-2 carboxylic acid, 7-(2,2,2-trichloro-l-hydroxyethyl)-xanthone2- carboxylic acid,

7-(2,2-dichloro-l-hydroxyethyl)-xanthone-2- carboxylic acid, 7-((phenyl)hydroxymethyl)-xanthone-2-carboxylic acid, 7-((p-chlorophenyl)hydroxymethyl)-xanthone-2- carboxylic acid, 7-((p-methylphenyl)hydroxymethyl)-Xanthone-2- carboxylic acid, 7-( (p-methoxyphenyl )hydroxymethyl)-xanthone-2- carboxylic acid, 7-((p-thiomethoxyphenyl)hydroxymethyl)- xanthone-2-carboxylic acid, 7-((furyl)hydroxymethyl)-xanthone-2-carboxylic acid, 7-((pyrryl)hydroxymethyl)-xanthone-2-carboxylic acid, 7-((thienyl)hydroxymethyl)-xanthone-2-carboxylic acid, 7-((pyridyl )hydroxymethyl)-xanthone-2-carboxylic acid, 7-((imidazolyl)hydroxymethyl)-xanthone-2- carboxylic acid, 7-((oxazolyl )hydroxymethyl )-xanthone-2-carboxylic acid.

EXAMPLE A solution of 4.1 g. of methyl 7-acetylxanthone2- carboxylate in 120 ml. of tetrahydrofuran is stirred at 0C and 6.8 ml. of 3M methylmagnesium bromide solution in ether are added dropwise. After stirring at 0C for 30 minutes, the reaction mixture is left to warm up' to room temperature. A saturated, ammonium chloride solution (50 ml.) is then added and the mixture is concentrated in vacuo. Extraction with ethyl acetate followed by evaporation yields methyl 7-( l-hydroxy-lmethylethyl)-xanthone-2-carboxylate.

The foregoing procedure is practiced upon the other 7-acyl methyl esters prepared as described in Example 3 to give the following products, through their respective methyl esters:

7-( l-hydroxy-l-methyl-n-propyl)-xanthone-2- carboxylic acid,

7-( l -hydroxyl -methyl-n-butyl )-xanthone-2- carboxylic acid,

7-( l-hydroxy-l-methyl-isobutyl)-xanthone-2- carboxylic acid,

7-( l-hydroxy-l-methyl-n-pentyl)-xanthone-2- carboxylic acid,

7-( l-hydroxy-l-methyl-isopentyl)-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-sec-pentyl)-xanthone-2- carboxylic acid,

7-( l-hydroxy-l-methyl-t-pentyl)-xanthone-2- carboxylic acid,

7-( l-hydroxy-l-methyl-n-hexyl)-xanthone-2- carboxylic acid,

7-( l-hydroxyl-methyl-n-heptyl)-xanthone-2 carboxylic acid,

7-( l-hydroxy-l-methyl-n-octyl)-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-n-nonyl)-xanthone-2- carboxylic acid,

7-( l-hydroxy-l-cyclopropylethyl)-xanthone-2- carboxylic acid,

7-( 1-hydroxy l -cyclobutylethyl )-xanthone-2- carboxylic acid,

7-( l-hydroxyl -c'yclopentylethyl )-xanthone-2- carboxylic acid,

7-( l-hydroxy-l-cyclohexylethyl )-xanthone-2- carboxylic acid,

7-( l-hydroxyl -trifluoromethylethyl)-xanthone-2- carboxylic acid,

7-( l-hydr0xy-l-difluoromethylethyl )-xanthone-2- carboxylic acid,

7-( lhy'droxyl -trichloromethylethyl)-xanthone-2- carboxylic acid,

7-( 1-hydroxy-1-dichloromethylethyl)-xanthonel2- carboxylic acid,

7-( l-hydroxy-l-phenylethyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-l-p-chlorophenylethyl xanthonel2- carboxylic acid,

7-( l-hydroxy-l-p-methylphenylethyl )-xanth0ne-2- carboxylic acid,

7-( l-hydroxy-l-p-methoxyphenylethyl)-xanthone-2- carboxylic acid,

7-( l-hydroxy-l-p-thiomethoxyphenylethyl)- xanthone-Z-carboxylic acid,

7-( l-hydroxy-lfurylethyl)xanthone-2-carboxylic acid,

7-( l-hydroxyl -pvrylethyl )xanthone-Z-carboxylic acid,

7-( l-hydroxy-l-thienylethyl)-xanthone l-carboxylic acid,

7-( l-hydroxyl -pyridylethyl)-xanthone-2-carboxylic acid,

7-( 1-hydroxy-1-imidazolyethyl)-xanthone-2- carboxylic acid,

7-( l-hydroxyl -oxazolylethyl)-xanthone-2- carboxylic acid.

EXAMPLE 6 The procedure of Example 5 is repeated employing, in lieu of methyl magnesium bromide, the reagents listed in Column C below to prepare the products listed in Column D below.

Column C Column D n-propylmagnesium bromide isopropylmagne'sium bromide n-butylmagnesium bromide isobutylmagnesium bromide sec-butylmagnesium bromide xanthone-Z-carboxylic) acid, and so forth,

-Continued Column C Column D 7-( l-hydroxy-l -t-butylethyl xanthone-Z-carboxylic acid,

7-( l-hydroxyl t-but \,'l-n-propyl xanthonelcarboxylic acid, and so forth, 7-(l-hydroxy-1-n-pentylethyl)- xanthone-Z-carboxylic acid,

7-( l-hydroxy-l-npentyLn-propyl i uinthone-l-carboxylic acid. and so 7-( l-hydroxy-I-hexylethyl)-xanthone- 2-carboxylic acid,

7-( l-hydroxy-l -hexyl-n-propyl xanthone-Z-carboxylic acid, and so forth,

7-( i-hydroxyl -heptylethyl) xanthone-Z-carboxylic acid,

7-( l-hydroxy-l-hepty|nprpyl)- xanthone-Z-carboxylic acid, and so forth,

7-( l-hydroxy-1-octylethyl)-xanthone- Z-carboxylic acid,

7-( l-hydroxy -octyl-n-propyl)' xanthone-Z-carboxylic acid, and so forth,

7-( l-hydroxyl -cyclopropylethyl xanthone-2-carboxylic acid,

propyl )-xanthone-Z-carboxylic acid,

and so forth,

7-( l-hydroxy-l -cyclobutylethyl xanthonc-2-carboxylic acid.

74 l-hydroxyl cyclohutyl-n-propyl xanthone-Lcarhoxylic acid, and so forth.

7-( I -hydrox l -cyclopentylethyl xanthone-Z-carhoxylic acid.

propyl )-xanthone-2-carhoxylic acid.

and so forth.

xanthone-Z-carboxylic acid.

7-( l-hydroxyl -cyclohexyl-n-propyl xanthone-Z-carboxylic acid. and so forth.

tbutylmagnesium bromide n-pentylmagnesium bromide hexylmagnesium bromide heptylmagnesium bromide octylmagnesium bromide cyclopropylmagnesium bromide cyclobutylmagnesium bromide cyclopentylmagnesium bromide cyclohexylmagnesium bromide EXAMPLE 7 A mixture of methyl xanthene-Z-carboxylate (5.1 g. 7.0 g. of aluminum chloride, 3 g. of chloroacetyl chloride, and 100 ml. of dichloroethane is stirred at room temperature for four hours. After the addition of hydrochloric acid-ice followed by chloroform extraction, the mixture is filtered through alumina (Cl-l Cl and evaporated to give methyl 7-chloroacetylxanthene-2- carboxylate.

The thus-prepared compound is oxidized according to the procedure of the fourth paragraph of Example 2 to give methyl 7-chloroacetylxanthone-Z-carboxylate.

A mixture of 750 mg. of methyl 7- chloroacetylxanthone-Z-carboxylate, 200 mg. of sodium borohydride, and 75 m]. of tetrahydrofuran is stirred for one hour at room temperature. Tlc (CH Cl /AcOEt 9:1) indicates the reaction is complete. Excess sodium borohydride is destroyed by the dropwise addition of aqueous acetic acid percent). The mixture is concentrated in vacuo and extracted with ethyl acetate to give methyl 7-( l-hydroxy-2- chloroethyl)-xanthone-2-carboxylate.

A mixture of 750 mg. of methyl 7-(l-hydroxy-2- chloroethyl)-xanthone-2-carboxylate, 150 mg. of sodium hydride, 75 ml. of dimethylformamide is stirred for three hours at room temperature. Excess sodium hydride is destroyed by adding a few drops of acetic acid. The mixture is then diluted with water, extracted Withsthy aw kensshrstmaw rap d 90. set at I ica (CH CllAcOET; 9:1) to give methyl 7-( 1,2- oxidoethyl)-xanthone-2-carboxylate.

A mixture of 118 mg. of methyl 7-( l ,2-oxidoethyl)- xanthone-2-carboxylate, mg. of periodic acid, and 15 .ml. of tetrahydrofuran is stirred at room temperature for two hours. After this time, l5 ml. ofmethylene chloride is added, the mixture filtered through alumina (CH Cl and evaporated. The residue is crystallized from methylene chloridezmethanol to give methyl 7- formylxanthone-2-carboxylate.

A mixture of [.2 g. of methyl 7-formylxanthone-2- carboxylate, 10 ml. of 2N sodium hydroxide, and 90 ml. of ethanol is refluxed for 60 minutes. Then, it is acidified, cooled, and suction filtered to give 7-formylxanthone-Zcarboxylic acid.

Reduction thereof as described in the first paragraph of Example 4 gives 7-hydroxymethylxanthone-2- carboxylic acid.

Employing methyl 5-chloroacetylxanthene2- carboxylate, prepared as described above, in the above procedure, affords 5-formylxanthone-Z-carboxylic acid which can be reduced to S-hydroxymethylxanthone-2- carboxylic acid.

EXAMPLE 8 5-EthylxanthoneQ-carboxylic acid is prepared from l.3-dicarbomethoxy-4-bromobenzene and oethylphenol in accordance with the procedures set forth in Example 1 above.

A mixture of 4 g. of the thus-obtained 5-ethylxanthone-Z-carboxylic acid, 10 g. of methyl iodide, and 10 g. of potassium carbonate in 50 ml. of dimethylformamide is stirred at room temperature for a period of 16 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant mixture extracted with ethyl acetate. The extracts are filtered through alumina to give methyl 5-ethylxanthone-2-carboxylate which can be recrystallized from methanol.

A suspension of 2.5 g. of methyl 5-ethylxanthone-2- carboxylate and 2.5 g. of chromic oxide in ml. of acetic acid and 10 ml. of acetic anhydride is stirred at room temperature for a period of six hours. After monitoring the reaction by tlc indicates the absence of starting material, 10 ml. of isopropanol are added and the resultant mixture warmed on the steam bath. Water (200 ml.) is then added portionwise to the resultant mixture is cooled to room temperature. The precipitate is filtered off, washed, and dried to obtain methyl 5- acetylxanthone-2-carboxylate.

A mixture of 1.09 g. of methyl Sacetylxanthone-Z- carboxylate, 70 ml. of isopropanol, 5 ml. of saturated sodium carbonate solution, and 25 ml. of water is re fluxed for two hours. The resultant mixture is then acidified, cooled and the crystals filtered off, washed, and dried to give 5-acetylxanthone-2-carboxylic acid.

The foregoing procedures can be followed with other 5-substituted methyl compounds (prepared according to the procedures of Example 1) to give the corre sponding 5-acyl compounds, to wit:

5-propionylxanthone-2-carboxylic acid; S-n-butyrylxanthone-Z-carboxylic acid; 5-isobutyrylxanthone-2-carboxylic acid; 5-n-pentanoylxanthone-Z-carboxylic acid; 5-isopentanoylxanthone-Z-carboxylic acid; 5-sec-pentanoylxanthone2-carboxylic acid; 5 t pentanoylxanthone-2-carboxylic acid;

S-n-hexanoylxanthone-2-carboxylic acid; 5-n-heptanoylxanthone-2-carboxylic acid; 5-noctanoylxanthone-Z-carboxylic acid; 5-n-nonanoylxanthone-2-carboxylic acid; S-cyclopropylcarbonylxanthone-Lcarboxylic acid; 5-cyclobutylcarbonylxanthone-Z-carboxylic acid; 5-cyclopentylcarbonylxanthone-Z-carboxylic acid; 5-cyclohexylcarbonylxanthone-2-carboxylic acid; 5-trifluoroacetylxanthone-Z-carboxylic acid; 5-difluoroacetylxanthone-Z-carboxylic acid; 5-trichloroacetylxanthone-2-carboxylic acid; 5-dichloroacetylxanthone-2-carboxylic acid; 5-benzoylxanthone-Z-carboxylic acid; S-(p-chlorobenzoyl)-xanthone-2-carboxylic acid; S-(p-methylbenzoyl)-xanthone-2-carboxylic acid; 5-(p-methoxybenzoyl)-xanthone-2-carboxylic acid; S-(p-thiomethoxybenzoyl)-xanthone-2carboxylic acid; S-furoylxanthone-2-carboxylic acid; 5-pyrrolyxanthone-Z-carboxylic acid; 5-thenoylxanthone-Z-carboxylic acid; 5-pyridylcarbonylxanthone-Z-carboxylic acid; S-imidazolylcarbonylxanthone-2-carboxylic acid; 5-oxazolylcarbonylxanthone-2'carboxylic acid.

EXAMPLE 9 Methyl S acetylxanthone-2-carboxylate is treated in accordance with the procedure of the first paragraph of Example 4, to give methyl 5-( lhydroxyethyl)- xanthone-Z-carboxylate which is hydrolyzed in accordance with the second paragraph thereof to give 5-(1- hydroxyethyl)-xanthone-2-carboxylic acid.

The foregoing procedures can be followed with other S-acyl methyl esters prepared as described in Example 8 to give the corresponding S-(I-hydroxyalkyl) compounds through their methyl esters, to wit:

5-( l-hydroxy-n-propyl)-xanthone-2-carboxylic acid;

5 l-hydroxy-n-butyl)-xanthone-2-carboxylic acid;

5-( l-hydroxyisobutyl)-xanthone-2-carboxylic acid;

5-( l-hydrxy-n-pentyl)-xanthone-2-carboxylic acid;

-( l -hydroxyisopentyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-sec-pentyl-xanthone-2-carboxylic acid;

5-( l-hydroxy-t-pentyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-n-hexyl)-Xanthone-2 carboxylic.acid;

5-(l-hydroxy-n-heptyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-n-octyl)-xanthone-2-carboxylic acid;

5-(1-hydroxy-n-nonyl)-xanthone-2-carboxylic acid;

5-((cyclopropyl)hydroxymethyl)-xanthone-2- carboxylic acid; 5-((cyclobutyl)hydroxymethyl)-xanthone-2- carboxylic acid; 5-((cyclopentyl)hydroxymethyl)-xanthone-2- carboxylic acid; 5-((cyclohexyl)hydroxymethyl)-xanthone-2- carboxylic acid; 5-(2,2,2-trifluoro-1-hydroxyethyl)-xanthone-2- carboxylic acid; 5-(2,2-difluoro-l-hydroxyethyl)-xanthone-2- carboxylic acid; 5-(2,2,2-trichloro-l-hydroxyethyl)-xanthone-2- carboxylic acid;

5-( 2,2-dich1orol -hydroxyethyl )-xanthone-2- carboxylic acid; 5-((phenyl)hydroxymethyl)-xanthone-2-carboxylic acid 5-((p-chlorophenyl)hydroxymethyl)-xanthone-2- r xl a t a. a.

24 S-((p-methylphenyl )hydroxymethyl )-xanthone-2- carboxylic acid; 5-((p-methoxyphenyl)hydroxymethyl)-xanthone 2- carboxylic acid; 5-((p-thiomethoxyphenyl)hydroxymethyl)- xanthone-Z-carboxylicacid; 5-((furyl)hydroxymethyl)-xanthone-2-carboxylic acid; 5((pyrryl)hydroxymethyl)xanthone-2-carboxylic acid; 5-((thienyl)hydroxymethyl)-xanthone-2-carboxylic acid; 5'((pyridyl)hydroxymethyl)-xanthone-2-carboxylic acid; 5-((imidazolyl)hydroxymethyl)-xanthone-2- carboxylic acid; 5-((oxazolyl)hydroxymethyl)-xanthone2-carboxylic acid.

EXAMPLE l 0 Methyl 5-acetylxanthone-2-carboxylic acid is treated in accordance with the procedure of the first paragraph of Example 5 to give methyl 5-( l-hydroxy-lmethylethyl)-xanthone-2-carboxylate which is hydrolyzed in accordance with the second paragraph thereof to give 5-( l-hydroxy-l methylethyl )-xanlhone-2- carboxylic acid.

The foregoing procedure is practiced upon the other S-acyl methyl esters prepared as described in Example 8 to give the following products, through their respective methyl esters:

5-( l-hydroxy-l-methyl-n-propyl )-xanthone-2- carboxylic acid;

5-( l-hydroxy-l-me'thyl-n-butyl)-xanthone-2- carboxylic acid; 7 5-( l-hydroxyl -methyl-isobutyl )-xanthone-2- carboxylic acid; 1

5-( l-hydroxy- 1 -methyl-n-pentyl)-xanthone-2- carboxylic acid;

5-( l-hydroxyl -methyl'isopentyl)-xanthone-2- carboxylic acid; I 5-( l-hydroxy- 1 -methylsec-pentyl)-xanthone-2- carboxylic acid; 5-(l-hydroxy-1-methy-t-pentyl)-xanthone-2- carboxylic acid; 5-( l-hydroxy-l-methyl-n-hexyl)-xanthone-2- carboxylic acid; 5-(l-hydroxy-l-metl1yl-n-heptyll-xanthone-Z- carboxylic acid;

5-( l-hydroxy-l-methyl-n-octyl)-xanthone-2- carboxylic acid;

5-( l-hydroxy-l-methyl-n-nonyl)-xanthone-2- carboxylic acid;

5-( l-hydroxyl -cyclopropylethyl)-xanthone-2- carboxylic acid;

5-( l-hydroxy-1-cyclobutylethyl)-xanthone-2- carboxylic acid;

5-( l-hydroxy-l-cyclopentylethyl)-xanthone-2- carboxylic acid; I

5-( l-hydroxy-l-cyclohexylethyl)-xanthone-2- carboxylic acid;

5-( l-hydroxyl -trifluoromethylethyl)-xanthone-2- carboxylic acid;

5-( l-hydroXy-l-difluoromethylethyl )-xanthone-2- acid;

-( l-hydro xy- 1 -pyrrylethyl )-xanthone-2-carboxylic acid;

5-( l-hydroxy-l-thienylethyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-lpyridylethyl)-xanthone-2-carboxylic acid; 5-( l-hydroxy-l-imidazolylethyl)-xanthone-2- carboxylic acid; I 5-( l'hydroxy-l -oxazolylethyl')-xanthone-2- ex i a isla.

EXAMPLE 11 The procedure of Example is repeated employing, in lieu of methyl magnesium bromide, the reagents listed in Column C below to prepare the products listed in Column D below.

Column C Column D 5-( l-hydroxyl -ethylethyl )-xanthone- Z-carboxylic acid,

5-( l-hydroxy-l-ethyl-n-propyl)- xanthone 2-carboxylic acid, and so forth,

5-( l-hydroxy-l-n-npropylethyly xanthoneQ-carboxylic acid,

5-( l-hydroxyl -n-propyl-n-propyl)- xanthone-Z-carboxylic acid, and so forth,

5-( l-hydroxyi -isopropylethyl xanthone-Lcarboxylic acid,

5-( l-hydroxy-l-isopropyl-n-propyl xanthone-2-carboxylic acid, and so forth,

5-[ l-hydroxy-l-n-butylethyl)- xanthone-Lcarboxylic acid,

5-( l-hydroxyl -n-butyl-n-propyl xanthone-2-carboxylic acid, and so forth,

5-( l-hydroxy-l-isobutylethyl) xanthone-Z-carboxylic acid.

5-( l-hydroxyl -isobutyl-n-propyl xanthone-Z-caboxylic acid, and so forth,

5-( l-hydroxyl -sec-butylethyl)- xanthone-2-carboxylic acid,

5-( l-hydroxyl -sec-butyl-n-propyl xanthone-Z-carboxylic acid, and so forth.

5-( l-hydroxy-lt-butylethyl)- xanthone-Z-carboxylic acid,

5-( I-hydroxy-l-t-butyl-n-propyl)- xanthone-2-carboxyhc acid, and so forth,

5-( l-hydroxy l nper|tylethyl)- xanthone-Z-carboxylic acid,

5-( I-hydroxy-l-n pentyl-n-propyl)- xanthoneQ-carboxylic acid, and so forth ethylmagnesium bromide n-propylmagnesium bromide isopropylmagnesium bromide n-butylmagnesium bromide isobutylmagnesium bromide sec-butylmagnesium bromide t-butylmagnesium bromide n-pentylmagnesium bromide hexylmagnesium bromide 2-carboxylic acid, 5-( I-hydroxy-l-hexyl-n-propyl)- xanthone-Z-carboxylic acid, and so forth,

- Continued Column C (olumn l) hepfvlmagnesium bromide 5( l-hydroxyl heptylcihvl xanthone-l-curboxyltc acid,

S-l l-hydroxy-I-hcptyl-n-propyl l xanthone-Z-carhoxylic acid, and so forth.

5-( l-hydroxy-l-octylethyl )-xnnthone- Z-carboxylic acid,

5-( l-hydroxyl -octyl-n-propyl xanthone-Z-carboxylic acid, and so forth,

5-( l-h)'droxy-lcyclopropylethyl)- xanthone-2carboxylic acid.

5-( l-hydroxyl -c vclopropyl-npropylJ-xanthone-Z-carboxylic acid, and so forth,

5-( l-hydroxy-l-cyclobutylethyl) xanthone-Z-carboxylic acid,

5-( l-hydroxy- I -cyclohutyl-n-propyl xanthone-2-carboxylic acid. and so forth.

5-( l-hydroxy-l-cyclopentylethyhxanthonelcarboxylic acid,

propyl l-xanthone-Z-carhoxylic acid. and so forth.

54 l-hydroxy-l-cyclohexylm-propyl xanthone-l-carhox lic acid. and so 5-( l-hydroxyl-c clohex leth llxanthone-Z-carbox lic acid 5( l-h \'drox \l qclohenl n propyl txanthone-Z-carhoxylic acid. and so forth.

octylmagnesium bromide cyclopropylmagnesium bromide cyclobutylmagnesium bromide cyclopentylmagnesium bromide cyclohexylmagnesium bromide cyclohexylmagnesium bromide EXAMPLE l2 Methyl 5-methylxanthone-Z-carboxylate is prepared by the procedure of Example 1 from o-methylphenol, followed by the preparation of the methyl ester of the thus-produced acid.

To a solution of 2.4 g. of methyl 5-methylxanthone-2- carboxylate in 30 ml. acetic acid and 30 ml. acetic anhydride are added 4.8 ml. concentrated sulfuric acid at 0C. After the addition of 5.6 g. of chromic acid, the mixture is stirred for five hours. The crude diacetoxymethyl intermediate is isolated by diluting the reaction mexture with water and filtering off the precipitate. The formyl derivative is obtained by refluxing the diacetoxymethyl compound thus obtained with 10 ml. 2N sulfuric acid in ml. methanol for 30 minutes, cooling, diluting with 60 ml. water and filtering off the precipitate to give 5-formylxanth0ne-2-carboxylic acid. This compound can be reduced as described above to S-hydroxymethylxanthone-Z-carboxylic acid.

7-Formylxanthone-Z-carboxylic acid is prepared by the above procedure, preferably by using 30 ml. of 2N sulfuric acid in 70 ml. of ethanol for two hour treatment of the diacetate.

EXAMPLE 13 A mixture of 51.5 g. of l,3-dimethyl-4-iodobenzene (4-iodo-m-xylene), 40 g. of o-formylphenol, 16 g. of cuprous oxide in 300 ml. of dimethylacetamide is heated to the boiling point and maintained under reflux (190C) for I44 hours with stirring and under a nitrogen atmosphere. The reaction' mixture is then poured into ice water and extracted with ether and the extracts are filtered through 500 g. of alumina in hexane to give l,3-dimethyl-4-o-formylphenyloxy)-benzene.

A mixture of 41 g. of 1,3-dimethyl-4-(o-formylphenyloxy)-benzene, 300 g. of potassium permanganate, 500 ml. of t-butanol, and 750 ml. of water is heated to the boiling point and maintained thereat for a period of three hours. After distilling off the t- EXAMPLE 14 A mixture of 2.84 ml. of o-ethylphenol, 5.0 g. of l,3- dicarbomethoxy-4-bromobenzene and 1.31 g. of cuprous oxide in 100 ml. of dimethylacetamide is stirred under reflux overnight. The resultant mixture is then poured on ice and extracted with ether. The ether extracts are washed with water and'2N aqueous sodium 'hydroxide. The washed extracts are dried and evaporated to give l,3-dicarbomethoxy-4-(o-ethylphenyloxy)-benzene which 'can be purified by chromatography through alumina with gradient elution with benzene:- hexane (50:50 60:40).

A mixture of 24 g. of l,2-dicarbomethxy-4-(o-ethylphenyloxy)-benzene, 20 g. ofpotassium hydroxide, 300 ml. of ethanol and 20 ml. of water are heated on a steam bath for about one-half hour. After this time, the reaction mixture is acidified with dilute hydrochloric acid and the ethanol evaporated. The resultant mixture is then extracted with ethyl acetate and the extracts are dried and evaporated to give l,3-dicarboxy-4-(o-ethylphenyloxy)-benzene which can be crystallized from methanolzethyl acetate A mixture of 1.94 g. of l,3-dicarboxy-4-(o-ethylphenyloxy)-benzene, 40 ml. of sulfolane and 30 ml. of polyphosphoric acid is stirred at 160C for 30 minutes. The resultant mixture is then diluted with water and the diluted mixture filtered. The precipitate is washed neutral, and then dissolved and heated in ethanol containing charcoal. The resultant mixture is then filtered, and the ethanol is partially evaporated. Water is added until crystallization starts. Filtration gives the solid product ethylxanthone-Z-carboxylic acid which can be recrystallized from ethanol.

The foregoing product is useful as described in Example 8 et seq.

In like manner, the foregoing reactions can be conducted using an alternate l,3-dicarboalkoxy-4- halobenzene starting material such as 1,3-dicarboxy-4- bromobenzene, l,3-dicarboethoxy-4-iodobenzene, and so forth, with similar results.

Upon substituting the other phenol starting compounds in the process of the preceding example, there are obtained the corresponding C-5 and O7 substituted xanthone-2-carboxylic acids.

EXAMPLE vent. The resultant mixture is extracted with methylene chloride and washed with bicarbonate and water. The washed extracts are concentrated to give methyl 7-( lhydroxyethyl)-xanthene-2-carboxylate.

A solution of 5.5 g. of methyl 7-(1- hydroxyethyl)xanthene-2-carboxylate in 100 ml. of pyridine is cooled in an ice bath. To the cooled solution are added 2.91 ml. of acetyl chloride and the resultant mixture is stirred in an ice bath for one-half hour and then at room temperature for one hour. After this time. the reaction mixture is poured into dilute hydrochloric acid-ice and the precipitate is filtered off and washed to give methyl 7-( l -acetoxyethyll-xanthcne-Z- carboxylate.

To a solution of 3 g. of methyl 7-(lacetoxyethyl)xanthene-IZ-carboxylate in 80 ml. of acetone are added 12 ml. of 8N chromic acid in 8N sulfuric acid. The resultant mixture is stirred at room temperature for] A hours. Excess chromic oxide is decomposed with aqueous sodium bisulfite and to the resultant mixture are added 500 ml. of water. The resultant mixture is stripped of solvent and extracted with methylene chloride. The methylene chloride extracts are washed with 10% aqueous sodium bicarbonate solution and the washed extracts are concentrated in vacuum to give methyl 7-( l-acetoxyethyl)xanthone-Z- carboxylate.

A solution of 2.70 g. of methyl 7-(lpresent example, the corresponding (l-hydroxyalkyhxanthone-2-carboxylic acid compounds are prepared.

EXAMPLE 16 A mixture of 4.5 g. of 7-acetylxanthone-Z-carboxylic acid, 10 g. of methyl iodide, and 10 g. of lithium carbonate in ml. of dimeth'ylformamide is stirred at room temperature for a period of 18 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant precipitate is filtered off and washed to give methyl 7- acetylxanthone-Z-carboxylate.

The foregoing procedure is repeated using the alternate lower alkyl iodides so as to prepare the corresponding lower alkyl acid esters hereof. e.g., ethyl 7- acetylxanthone-Z-carboxylate, n-propyl 7- acetylxanthone-Z-carboxylate, isopropyl 7- acetylxanthone-Z-carboxylate, n-propyl 7- acetylxanthone-2-carboxylate, isobutyl 7- acetylxanthone-Z-carboxylate, sec-butyl 7- acetylxanthone-2-carboxylate, t-butyl 7- acetylxanthone-Z-carboxylate. n-pentyl 7- acetylxanthone-2-carboxylate, and so forth.

In like manner. the other xanthone-Z-carboxylic acids thereof containing substituents at the C-5 or (-7 positions, prepared as described above, can be converted to the corresponding acid esters.

EXAMPLE 17 To a solution of 10 g. of 7-acetylxanthone-2- carboxylic acid in 200 ml. of ethanol is added the theoretical amount of sodium hydroxide dissolved in 200 ml. of 90 percent ethanol. The reaction mixture is then concentrated in vacuum to give sodium 7- acetylxanthone-2-carboxylate.

Sodium 7-(l-hydroxyethyl)-xanthone-2-carboxylate and sodium 5-acetylxanthone-Z-carboxylate are also thus prepared.

In a similar manner, the potassium and lithium salts are prepared. Similarly, by replacing the sodium salt by means of an appropriate metal salt reagent, e.g., calcium chloride, manganese chloride, and so forth, the other xanthone-Z-carboxylic acid salts are prepared,

e.g., magnesium 7-acetylxanthone-Z-carboxylate, calcium 7-acetylxanthone-2-carboxylate, aluminum 7- acetylxanthone-Z-carboxylate, ferrous 7- acetylxanthone-2-carboxylate, zinc 7-acetylxanthone- 2-carboxylate, manganese 7-acetylxanthone-2- carboxylate, ferric 7-acetylxanthone-Z-carboxylate, and so forth.

In a similar manner, the xanthone-2-carboxylic acid salts of the other C-S or C-7- substituted xanthone-2- carboxylic acids hereof are prepared.

EXAMPLE 18' To a mixture of 50 ml. of concentrated aqueous ammonia in 500 ml. of methanol there are added 20 g. of 5-acetylxanthone-2-carboxylic acid. The resultant mixture is stirred for two hours and is then evaporated to dryness to give the ammonium salt of 5'acetylxanthone-Z-carboxylic acid.

A solution of g. of xanthone-2-carboxylic acid in 50ml. of thionyl chloride is heated at reflux for one hour. Thereafter, the solution is evaporated to dryness to give the corresponding acid chloride to which is added a concentrated ethereal ammonia solution. The resultant solution is evaporated giving; the ammonium salt of xanthone-Z-carboxylic acid.

In like manner, the lower alkyl amides can be prepared using monoalkylamine or dialkylamine in lieu of ammonia in the above procedures. Thus prepared, e.g.,

are

7-propionylxanthone-2-carboxylic acid amide, N-methyl 7-isobutyrylxanthone-Z-carboxylic acid amide, f N,N-dimethy l 5-( l-hydroxyethyl)-xanthone-2- carboxylic acid amide, N.,N-diethyl 7-(,l-hydroxy-l-methyl)-xanthone-2- carboxylic acid amide, N-ethyl 7-benzoylxanthone-2-carboxylic acid amide, N-n-propyl 7-furylxanthone-Z-carboxylic acid amide,

and so forth.

EXAMPLE 19 To a mixture of 20 g. of procaine and 500 ml. of aqueous methanol are added 20 g. of 7- isobutyrylxanthone-2-carboxylic acid. The resultant mixture is stirredat room temperature for 16 hours. It is then evaporated under reduced pressure to give the procaine salt of 7-isobutyrylxanthone-Z-carboxylic acid. l

Similarly, the lysine, caffeine, and arginine salts thereof are obtained. In like manner, the e.g., procaine, Lys n saf s sad a i i the sthstfi-ja l 7-substituted xanthone-Z-carboxylic acids are obtained, e.g., the procaine salt of 7-acetylxanthonc-2- carboxylic acid, the caffeine salt of 5-(l-hydroxy-npropyl)xanthone-Z-carboxylic acid, the lysine salt of 7-hydroxymethylxanthone-2-carboxylic acid, the procaine salt of 5-hydroxymethylxanthone-Z-carboxylic acid, and the arginine salt of 5-acetylxanthone-2- carboxylic acid.

EXAMPLE 20 The following procedures illustrate the method by which the pharmaceutical compositions'of the compounds hereof are prepared.

Sodium chloride (0.44 g.) is dissolved in ml. of a (9.47 g./l. water)'sodium hydrogen phosphate solution. A sodium dihydrogen phosphate (8.00 g./l. water) solution (20 ml.) is then added thereto. The resultant solution having a pH of 7.38 is sterilized in an autoclave. This vehicle is then added to solid. dry xanthone-2- carboxylic acid to give a preparation suitable for intravenous injection containing 2.5 mg. of xanthone-Z- carboxylic acid per ml. of total composition. 7

EXAMPLE 2l The following procedure illustrates a test procedure for the compounds hereof. Y

Normal female (Sprague-Dawley) rats of 150 to 200 grams each are passively sensitized intradermally by injection of rat anti-egg albumin reaginic sera. After 24 hours, each rat is challenged intravenously with 1.75 ml. of 0.4 percent Evans blue, 1 mg. egg albumin plus 10.0 mg. of xanthone-2-carboxylic acid. Control rats receive no xanthone-Z-carboxylic acid. The dermal bluing is recorded 15 to 25 minutes later. The rats which receive the xanthone-2-carboxylic acid exhibit a percent inhibition of allergic reaction whereas the control rats exhibit no inhibition.

The above procedure is repeated, using 7-acetylxanthone-2-carboxylic acid, with similar results. The above procedure is repeated .using oral administration, with similar results. Xanthone-2-carboxylic acid compounds are administered by gavage at a dose of 20 mg.per animal l5 minutes prior to challenge. Twenty to 30 minutes after challenge the degree of dermal bluing isread, with similar results.

inhibition of reaginic antigen-antibody reactions in' rats is regarded as representative of inhibition of human reaginic antigen-antibody reactions which occur during allergic episodes.

Subjects challenged by antigen inhalation are 'measured for the extent of provoked degree of asthma condition by changes in airway resistance on expiration. The subject compounds are administered as an aerosol by inhalation before antigen challenge. Prevention of asthmatic conditions upon the administration of the compounds is evidence by a decrease in airway resistance and other subjective improvements, e.g., reduced cough.

What is claimed is:

1. A method for inhibiting the symptoms of the asth matic condition resulting from an antigen-antibody reaction in a host susceptible to said reaction which comprises administering to said host an effective amount of from about 0.005 to about 100 mg. per kg. of body weight per day sufficient to produce said inhibition of a nas nsl..rsers ta P) the ma es;

coon R 2. The method according to claim 1 wherein the compound is the compound of formula (A) in which R is lower alkyl.

3. The method according to claim 1 wherein the COOH compound is 5-formylxanthone-Z-carboxylic acid.

4. The method according to claim 1 wherein the compound is 5-cyclopropylcarbonylxanthone-Z- carboxylic acid.

5. The method according to claim 1 wherein the compound is S-acetylxanthone-2-carboxylic acid.

6. The method according to claim 1 wherein the compound is the compound of formula (B) in which R is lower alkyl.

7. The method according to claim 1 wherein the compound is 7-formylxanthone-Z-carboxylic acid..

8. The method according to claim 1 wherein the compound is 7-cyclopropylcarbonylxanthone-2- carboxylic acid.

9. The method according to claim 1 wherein the compound is 7-acetylxanthone-2-carboxylic acid.

10. The method according to claim 1 wherein the compound is sodium 7-acetylxanthoneQ-carboxylate. l l =l UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION patent 3,873,714 Dated March 25, 1975 Inventor) Jurg R. Pfister, Ian T. Harrison, John H. Fried It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 15, line 34, "iosmers" should read isomers Column 17, line 29, "acetylxanthonel2" should read acetylxanthone-Z- Column 18, line 19, "acetylxanthonel2" should read acetylxanthone-Z- Column 20, line ll,

. "xanthonel2-" should read xanthone-Z- Column 20,

line 15, "xanthonel2" should read xanthone-Z- Column 26, lines 20-24, delete:

"cyclohexylmagnesium "5-(lhydroxy-l-cyclohexylethyl) bromide" xanthone-Z-carboxylic acid 5- (l-hydroxy-l-cyclohexyl-n-propyl) xanthone-Z-carboxylic acid, and so" Signed and Scaled this twenty-first Day Of October 1975 [SEAL] Attest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner ofPatents and Trademarks I. i O 

1. A METHOD FOR INHIBITING THE SYMTOMS OF THE ASTHMATIC CONDITION RESULTING FROM AN ANTIGEN-ANTIBODY REACTION IN A HOST SUSCEPTIBLE TO SAID REACTION WHICH COMPRISES ADMINISTERING TO SAID HOST AN EFFECTIVE AMOUNT TO FROM ABOUT 0.005 TO ABOUT 100 MG. PER KG. OF BODY WEIGHT PER DAY SUFFICIENT TO PRODUCE SAID INHIBITION OF A COMPOUND REPRESENTED BY THE FORMULAS:
 2. The method according to claim 1 wherein the compound is the compound of formula (A) in which R2 is lower alkyl.
 3. The method according to claim 1 wherein the compound is 5-formylxanthone-2-carboxylic acid.
 4. The method according to claim 1 wherein the compound is 5-cyclopropylcarbonylxanthone-2-carboxylic acid.
 5. The method according to claim 1 wherein the compound is 5-acetylxanthone-2-carboxylic acid.
 6. The method according to claim 1 wherein the compound is the compound of formula (B) in which R2 is lower alkyl.
 7. The method according to claim 1 wherein the compound is 7-formylxanthone-2-carboxylic acid.
 8. The method according to claim 1 wherein the compound is 7-cyclopropylcarbonylxanthone-2-carboxylic acid.
 9. The method according to claim 1 wherein the compound is 7-acetylxanthone-2-carboxylic acid.
 10. The method according to claim 1 wherein the compound is sodium 7-acetylxanthone-2-carboxylate. 